WO2000044712A1 - N-hydroxyformamide derivatives as inhibitors of matrix metalloproteinases - Google Patents

Abstract

Compounds having formula (I) are matrix metalloproteinase inhibitors. Also disclosed are matrix metalloproteinase-inhibiting compositions and methods of inhibiting matrix metalloproteinase in a mammal.

Description

N-HYDROXYFORMAMIDE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES

Technical Field This invention relates to compounds having activity to inhibit matrix metalloproteinases, to pharmaceutical compositions comprising these compounds and to a medical method of treatment. More particularly, this invention concerns reverse hydroxamate-containing compounds which inhibit matrix metalloproteinases, pharmaceutical compositions comprising the compounds, and methods of inhibiting matrix metalloproteinases in a mammal.

Background of the Invention The matrix metalloproteinases (MMP's) are a class of extracellular enzymes including collagenase, stromelysin, and gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.

Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins. In healthy tissue, there is a continual and delicately-balanced series of processes which include cell division, matrix synthesis and matrix degradation. In certain pathological conditions, an imbalance of these three processes can lead to improper tissue restructuring. In arthritis, for example, joint mobility can be lost when there is improper remodeling of load-bearing joint cartilage. With cancer, lack of coordination of cell division and the two processes of matrix synthesis and degradation may lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries which, in turn, may lead to subsequent metastasis.

There has been heightened interest in discovering therapeutic agents which bind to and inhibit MMP's. The discovery of new therapeutic agents possessing this activity will lead to new drugs having a novel mechanism of action for combating disease states involving tissue degenerative processes including, for example, rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration, and tumor growth and metastasis or invasion.

Summary of the Invention In its principle embodiment, the present invention provides a matrix metalloproteinase inhibitory compound of formula (I),

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 and R 2 are independently selected from the group consisting of (1) hydrogen,

(2) alkyl,

(3) alkenyl,

(4) alkynyl,

(5) alkoxyalkyl, (6) alkoxycarbonylalkyl,

(7) haloalkyl,

(8) hydroxyalkyl,

(9) -(alkylene)-S(O)_p-alkyl, wherein p is zero to two,

(10) phenyl, (11) phenylalkoxyalkyl,

(12) phenylalkyl,

(13) phenoxyalkyl,

(14) -(alkylene)-N(R2o)SO2-phenyl, wherein R20 is hydrogen or alkyl,

(15) (heterocycle)oxyalkyl, (16) -(alkylene)-S(O)_p-heterocycle,

(17) -(alkylene)-heterocycle,

(18) heterocycle, and

(19) -(alkylene)-NR⁶R , wherein for (15)-(18), the heterocycle is selected from the group consisting of

(a) pyridyl,

(b) pyrazinyl,

(c) pyridazinyl,

(d) furyl, (e) thienyl,

(f) isoxazolyl,

(g) oxazolyl, (h) thiazolyl, (i) isothiazolyl

0)

wherein X is selected from the group consisting of -O-,

-NR 5 SO₂-, -S(O)_p-, and -C(O)-, and Y 2 is selected from the group consisting of a covalent bond, -O-, alkylene of two to four carbon atoms, piperidineneyl, alkenylene of two carbon atoms, alkynylene of two carbon atoms, -S(O)_p-,and -C(O)-, and

and wherein for (10)-(18), the phenyl and the phenyl part of the phenylalkoxy alkyl, the

20 phenylalkyl, -the (alkylene)-N(R )SO₂-phenyl, the phenoxyalkyl, and the - (alkylene)-S(O)_p-phenyl, the heterocycle, and the heterocycle part of the (heterocycle)oxyalkyl, the -(alkylene)-heterocycle and the -(alkylene)-S(O)_p- heterocycle are optionally substituted with one, two, or three substituents independently selected from the group consisting of

(a) alkyl,

(b) alkoxy,

(c) alkoxyalkyl,

(d) halo, (e) haloalkyl,

(f) hydroxy,

(g) hydroxyalkyl,

(h) -(alkylene)-heterocycle, (i) -(alkylene)-phenyl, (j) -N(R²°)SO₂-alkyl,

(k) phenyl, wherein the phenyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of

(i) cyano,

(ii) nitro, and

(iii) halo, (1) -C(O)OR²°, and (m) -C(O)NR^xR^y, wherein R^x and R^y are independently selected from the group consisting of (i) alkyl, (ii) phenyl, and

(iii) phenylalkyl, wherein for (ii) and (iii), the phenyl and the phenyl part of phenylalkyl are optionally substituted with substituents independently selected from the group consisting of (a) halo, and

(b) alkoxy, and wherein for (19), R and R are independently selected from the group consisting of

(a) hydrogen, (b) alkyl,

(c) cycloalkyl,

(d) cycloalkylalkyl,

(e) alkanoyl,

(f) phenyl, and

(g) phenylalkyl, wherein for (f) and (g), the phenyl and the phenyl part of the phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl,

(ii) alkoxy, (iii) perfluoroalkyl, (iv) halo, (v) haloalkyl, and

(vi) alkanoyl, or

R and R , taken together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of (a) morpholinyl,

(b) thiomorpholinyl, (c) thiomorpholinyl sulfone,

(d) pyrrolidinyl,

(e) piperazinyl,

(f) piperidinyl,

(g) succinimidyl,

(h) maleimidyl,

(i) glutarimidyl,

(j) phthalimidyl,

(k) naphthalimidyl,

wherein for (a)-(w), the groups defined by R and R , together with the nitrogen atom to which they are attached, are optionally substituted with one or two substituents independently selected from the group consisting of (i) halo,

(ϋ) alkyl,

(iii) alkoxy,

(iv) phenoxy,

(v) phenylalkyl, and

(vi) benzyloxy;

R is selected from the group consisting of

(1) hydrogen, (2) alkyl, and

(3) hydroxyalkyl; or R 2 and R 3 , taken together with the carbon atom to which they are attached, form a dioxanyl ring; or

R 1 and R 3 taken together with the carbon atoms to which they are attached form a 5, 6, or 7-membered saturated carbocyclic ring;

R and R are independently selected from the group consisting of

(1) hydrogen,

(2) alkyl, (3) perfluoroalkyl,

(4) halo,

(5) haloalkyl,

(6) alkoxy,

(7) hydroxy, (8) hydroxyalkyl,

(9) alkoxy alkyl, and

(10) nitro;

X is selected from the group consisting of

(1) -CH₂SO₂-,

and

(3) -NR 8 SO₂-, wherein R 8 is either hydrogen or alkyl; wherein each group is drawn with its left-hand end being the end which attaches to the

2 3 ccaarrbboonn ccoonnttaaiiining R and R^" , and its right-hand end being the end which attaches to the phenyl group;

Y is selected from the group consisting of ( 1 ) a covalent bond,

(2) -O-,

(3) alkylene-of two to four carbon atoms,

(4) piperidineneyl,

(5) alkenylene of two carbon atoms, (6) alkynylene of two carbon atoms,

(7) -SO2-, (8) -NHC(O)-, and

(9) -C(O)-;

is selected from the group consisting of

(1) phenyl,

(2) pyridyl,

(3) pyrazinyl,

(4) pyridazinyl, (5) furyl,

(6) thienyl,

(7) isoxazolyl,

(8) oxazolyl,

(9) thiazolyl, and

(10) isothiazolyl, wherein (1)-(10) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of (a) alkyl, (b) alkoxy, wherein the alkoxy can be optionally substituted with alkoxy,

(c) -(alkylene)-CO₂R⁸,

9 10 9 10

(d) -(alkylene)-NR R , wherein R and R are independently selected from the group consisting of

(i) alkyl, (ii) phenyl, and

(iii) phenylalkyl, wherein for (ii) and (iii), the phenyl and the phenyl part of the phenylalkyl can be optionally substituted with one or two substituents independently selected from the group consisting of halo and alkoxy,

(e) alkoxyalkyl,

(f) cyano,

(g) cyanoalkyl, (h) halo, (i) haloalkyl,

(j) hydroxy, (k) hydroxyalkyl, (1) thioalkoxy, (m) thioalkoxy alkyl, (n) phenylalkoxy, (o) phenoxy,

(p) phenoxyalkyl, (q) (heterocycle)oxy, (r) (heterocycle)oxyalkyl, (s) perfluoroalkyl, (t) perfluoroalkoxy,

(u) sulfinylalkyl, (v) sulfonylalkyl,

(w) > — o , wherein A is selected from the group consisting of -CH₂-, -CH₂O- and

-O-, and B is selected from the group consisting of -C(O)- and -(C(R")2)_V -, wherein R" is either hydrogen or alkyl, and v is 1-3, and

(x) -N(R )SO₂R , wherein R is selected from the group consisting of (i) hydrogen, (ϋ) alkyl, and

8 12 12

(iii) -N(R )(R ), wherein R is hydrogen or alkyl, wherein for (q) and (r), the heterocycle part of (heterocycle)oxy, and

(heterocycle)oxyalkyl are selected from the group consisting of

(i) pyridyl, (ii) pyrazinyl,

(iii) pyridazinyl,

(iv) furyl,

(v) thienyl,

(vi) isoxazolyl, (vii) oxazolyl,

(viii) thiazoloyl, and

(ix) isothiazolyl, and wherein for (q) and (r), the heterocycle part of the (heterocycle)oxy and the (heterocycle)oxyalkyl can be optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl, (ii) alkoxy,

(iii) perfluoroalkyl, (iv) halo, (v) cyano, (vi) cyanoalkyl, (vii) haloalkyl, and

(viii) alkanoyl, and wherein for (o) and (p), the phenyl part of the phenoxy and the phenoxy alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl, (ii) alkoxy, (iii) perfluoroalkyl, (iv) halo,

(v) cyano, (vi) cyanoalkyl, (vii) haloalkyl, and (viii) alkanoyl.

In another embodiment, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of compound of formula I in combination with a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides a method of inhibiting matrix metalloproteinases in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula I.

Detailed Description of the Invention As used throughout this specification and the appended claims, the following terms have the meanings specified:

The term "alkanoyl," as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group. The term "alkenyl," as used herein, represents a monovalent straight or branched chain group containing at least one carbon-carbon double bond.

The term "alkenylene," as used herein, represents a divalent group derived from a straight or branched chain hydrocarbon containing at least one double bond. The term "alkoxy," as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom. The alkoxy groups of this invention can be optionally substituted.

The term "alkoxy alkyl," as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkylene group. The term "alkoxycarbonyl," as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.

The term "alkoxycarbonylalkyl," as used herein, represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkylene group.

The term "alkyl," as used herein, represents a saturated straight or branched chain hydrocarbon radical.

The term "alkylene," as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms.

The term "alkynyl," as used herein, represents a monovalent straight or branched chain group containing at least one carbon-carbon triple bond.

The term "alkynylene," as used herein, represents a divalent group derived from a straight or branched chain hydrocarbon containing at least one triple bond.

The term "benzyloxy," as used herein, represents a benzyl group attached to the parent molecular moiety through an oxygen atom. The phenoxy groups of this invention can be optionally substituted.

The term "carbocycle," as used herein, represents a ring comprising 5, 6, or 7 carbon atoms and zero double bonds.

The term "cyano," as used herein, represents -CN.

The term "cyanoalkyl," as used herein, represents a cyano group attached to the parent molecular moiety through an alkyl group.

The term "cycloalkyl," as used herein, represents a saturated carbocyclic group having three to seven carbons.

The term "cycloalkylalkyl," as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group. The term "halo," as used herein, represents -F, -Cl, -Br, and -I.

The term "haloalkyl," as used herein, represents an alkyl group substituted by one, two, three, or four halogen atoms. The term "heterocycle," as used herein, represents a five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The five-membered ring has zero to two double bonds and the six- and seven-membered rings have zero to three double bonds. The heterocycle groups of this invention can be optionally substituted.

The term "(heterocycle)oxy," as used herein, represents a heterocycle group attached to the parent molecular moiety through an oxygen atom. The (heterocycle)oxy groups of this invention can be optionally substituted.

The term "(heterocycle)oxy alkyl," as used herein, represents a (heterocycle)oxy group attached to the parent molecular moiety through an alkyl group. The (heterocycle)oxyalkyl groups of this invention can be optionally substituted.

The term "hydroxy," as used herein, represents -OH.

The term "hydroxyalkyl," as used herein, represents a hydroxy group attached to the parent molecular moiety through an alkyl group. The term "nitro," as used herein, represents -NO₂.

The term "perfluoroalkoxy," as used herein, represents a perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.

The term "perfluoroalkyl," as used herein, represents an alkyl group wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. The term "pharmaceutically acceptable prodrug," as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of this invention.

The term "pharmaceutically acceptable salt," as used herein, represents salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

The term "phenoxy," as used herein, represents a phenyl group attached to the parent molecular moiety through an oxygen atom. The phenoxy groups of this invention can be optionally substituted.

The term "phenoxy alkyl," as used herein, represents a phenoxy goup attached to the parent molecular moiety through an alkyl group. The phenoxyalkyl groups of this invention can be optionally substituted. The term "phenylalkoxy," as used herein, represents a phenyl group attached to the parent molecular moiety through an alkoxy group. The phenylalkoxy groups of this invention can be optionally substituted.

The term "phenylalkoxyalkyl," as used herein, represents a phenylalkoxy group attached to the parent molecular moiety through an alkylene group. The phenylalkoxyalkyl groups of this invention can be optionally substituted.

The term "phenylalkyl," as used herein, represents a phenyl group attached to the parent molecular moiety through an alkyl group. The phenylalkyl groups of this invention can be optionally substituted.

The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to parent compounds defined above, such as, by hydrolysis in blood.

The term "sulfinyl," as used herein, represents -S(O)-.

The term "sulfinylalkyl," as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfinyl group.

The term "sulfonyl," as used herein, represents -SO₂-. The term "sulfonylalkyl," as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfonyl group.

The term "thioalkoxy," as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfur atom.

The term "thioalkoxy alkyl," as used herein, represents a thioalkoxy group attached to the parent molecular moiety through an alkyl group.

Compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. These compounds are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtues thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers are designated (RS). Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

In accordance with methods of treatment and pharmaceutical compositions of the invention, the compounds can be administered alone or in combination with other matrix metalloproteinases inhibiting agents. When using the compounds, the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. The compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term "parenteral" includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.

Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.

The inhibitory effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is adminstering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or poly anhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.

Transdermal patches can also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.

Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents. Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. The total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg kg body weight or preferably from about 0.25 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.

Preferred for the practice of the instant invention are the following embodiments: compounds of formula (I), wherein R and R are hydrogen, compounds of formula (I), wherein Y is a covalent bond, compounds of formula (I), wherein X is -CH₂SO₂-, compounds of formula (I), wherein Y is -O-, compounds of formula (I), wherein R is hydrogen, compounds of formula (I), wherein R is alkyl, compounds of formula (I), wherein R is -(alkylene)-NR R , compounds of formula (I), wherein R and R , taken together with the carbon atoms to which they are attached, form a 5, 6, or 7-membered carbocyclic ring,

Specific compounds of the instant invention include, but are not limited to, hydroxy((lRS)-l-methyl-3-((4-phenoxyphenyl)sulfonyl)propyl)formamide, hydroxy((lRS)-l-methyl-3-((4-(4-

(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl)formamide,

(lRS)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)-l-methylpropyl(hydroxy)formamide,

( 1 R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4- phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide, hydroxy((lR)-3-((4-phenoxyphenyl)sulfonyl)-l-((3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl)formamide,

N-(2-(formyl(hydroxy)amino)ethyl)-N-methyl-4-(4-pyridinyloxy)benzenesulfonamide,

N-(4-(((2RS)-2-(formyl(hydroxy)arnino)-3-hydroxypropyl)sulfonyl)phenyl)-4-

(trifluoromethoxy)benzamide, N-(4-(((lRS)-2-(formyl(hydroxy)amino-l-

(hydroxymethyl)ethyl)sulfonyl)phenyl)benzamide,

N-(4-(((2RS)-2-(formyl(hydroxy)amino)-3-hydroxypropyl)sulfonyl)phenyl)-4- pentylbenzamide,

2,2-dimethyl-3-((4-phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide, ( 1 R)-3-((4-(4-chlorophenoxy)phenyl)sulfonyl)- 1 -((4,4-dimethyl-2,5-dioxo- 1 - imidazolidinyl)methyl)propyl(hydroxy)formamide,

2,2-dimethyl-3-((4-(4-

(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl(hydroxy)formamide,

(lR)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)-l-((3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl(hydroxy)formamide, ( 1 R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4'-(trifluoromethyl)( 1 , 1 '- biphenyl)-4-yl)sulfonyl)propyl(hydroxy)formamide,

(lRS)-2-(((4-(4-fluorophenoxy)phenyl)sulfonyl)methyl)-cyclohexyl(hydroxy)formamide, and hydroxy((5-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)- 1 ,3-dioxan-5- yl)methyl)formamide.

Determination of Biological Activity The efficacy of the compounds of the invention as matrix metalloproteinase inhibitors was determined by measuring inhibition as outlined below for Gelatinase A, a member of this family of enzymes. Recombinant active gelatinase-A (MMP-2) is purchased from Oncogene Research. The enzyme is assayed by its cleavage of a fluorescent substrate in 150 uL volume in a microfluor plate as described in Science 1990, 247, 954-958 . Upon cleavage of the substrate, the fluorescence of the EDANS group is increased 30-fold, and this increase is monitored using a f-max (Molecular Devices) fluorescent plate reader (ex: 335 nm; em: 485 nm). The rates of cleavage of the substrate by gelatinase-A in the presence or absence of inhibitors are measured in a 40 min assay at ambient temperature. Stock solutions of the compounds in DMSO are prepared, and these solutions are diluted into the assay buffer (50 mM Tris HC1, pH 7.4, with 150 mM NaCl and 10 mM CaCl₂), which is also used for dilution of the enzyme and substrate. The potencies of the compounds [IC₅₀], shown below in Table 1, are calculated by plotting the logit function of the percent inhibition data relative to control vs. the logarithm of the inhibitor concentrations.

Table 1: Inhibition of MMP-2

Synthetic Methods Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: DMSO for dimethylsulfoxide; MTBE for methyl tert-butyl ether, THF for tetrahydrofuran, m-CPBA for meta-chloroperbenzoic acid, DMF for N,N- dimethylformamide, LDA for lithium diisopropylamide, and NMP for N- methylpyrrolidinone.

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds of the invention can be prepared. The compounds can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-5. The groups R ,

R , R

are defined above. It will be readily apparent to one of ordinary skill in the art that the compounds can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below.

As shown in Scheme 1, compounds of formula (1) can be treated with base then reacted with compounds of formula (2) to provide compounds of formula (3). Representative bases include n-butyllithium, tert-butyllithium, lithium hexamethyldisilazide, and LDA. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, toluene, and hexanes. The reaction temperature is about -100 °C to 35 °C and depends on the method chosen. Reaction times are typically 1-36 hours. In a preferred embodiment, compounds of formula (1) in THF at -78 °C are treated with n-butyllithium for 15 minutes, treated with compounds of formula (2), warmed to 23 °C, and stirred for 16 hours to provide compounds of formula (3). Compounds of formula (3) can be converted to compounds of formula (4) by treatment with tert-butyl N-(tert-butoxycarbonyloxy)carbamate, triphenylphosphine, and diethyldiazocarbodiimide. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, and dichloromethane. The reaction temperature is about -10 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5-24 hours. In a preferred embodiment, compounds of formula (3) in THF at 0 °C are treated with tert-butyl N-(tert-butoxycarbonyloxy)carbamate, triphenylphosphine, and diethyldiazocarbodiimide , warmed to room room temperature, and stirred for 2 hours to provide compounds of formula (4).

Conversion of compounds of formula (4) to compounds of formula (5) can be accomplished by deprotection with acid. Representative acids include trifluoroacetic acid, HC1, and H₂SO . Examples of solvents used in these reactions include dichloromethane, chloroform, carbon tetrachloride, and dichloroethane. The reaction temperature is about -20 °C to 30 °C and depends on the method chosen. Reaction times are typically 0.5-24 hours. In a preferred embodiment, compounds of formula (4) in dichloromethane at 0 °C are treated with trifluoroacetic acid, warmed to room temperature, and stirred for 1 hour to provide compounds of formula (5).

Compounds of formula (5) can be converted to compounds of formula (6) by treatment with a formylating agent. Representative formylating agents include acetic formic anhydride and 2,2,2-trifluoroethyl formate. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, and dioxane. The reaction temperature is about -20 °C to 30 °C and depends on the method chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (5) in THF at 0 °C are treated with acetic formic anhydride and stirred for 20 minutes to provide compounds of formula (6).

Scheme 1

1 1

The preparation of compounds where R is -(alkylene)-NR R is shown in Scheme 2. Compounds of formula (7), prepared as described in Scheme 1, can be converted to compounds of formula (8) by deprotection of the benzyl group. Representative deprotection conditions include H₂/Pd-C, Raney nickel, Na/NH₃, and ozone. Examples of solvents used in these reactions include methanol, ethanol, isopropanol, and tert-butanol. The reaction temperature is about 20 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5-24 hours. In a preferred embodiment, compounds of formula (7) in methanol and acetic acid at room temperature were treated with 10% Pd carbon under 60 psi of hydrogen for 4 hours to provide compounds of formula (8). Conversion of compounds of formula (8) to compounds of formula (9) can be accomplished by treatment with a substituted amine (HNR R ) in the presence of triphenylphosphine and diethyldiazocarbodiimide. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, and dichloromethane. The reaction temperature is about -10 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5-25 hours. In a preferred embodiment, compounds of formula (8) in THF at 0 °C are treated with a substituted amine (HNR R ), triphenylphosphine, and diethyldiazocarbodiimide, warmed to room temperature, and stirred for 5 hours to provide compounds of formula (9).

Compounds of formula (9) can be converted to compounds of formula (10) using the methods described in Scheme 1.

Scheme 2

(10) (9) Scheme 3 shows the synthesis of compounds where X is -NR SO₂-. Compounds of formula (11) can be condensed with compounds of formula (12) in the presence of base to provide compounds of formula (12). Representative bases include triethylamine, diisopropylethylamine, pyridine, and imidazole. Examples of solvents used in these reactions include dichloromethane, chloroform, carbon tetrachloride, and 1,2- dichloroethane. The reaction temperature is about -10 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5-24 hours. In a preferred embodiment, compounds of formula (11) in dichloromethane at 0 °C are treated with compounds of formula (12) in the presence of triethylamine and stirred for 2.5 hours to provide compounds of formula (13). Compounds of formula (13) can be converted to compounds of formula (14) by treatment with a reducing agent. Representative reducing agents include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and borane. Examples of solvents include ethanol, methanol, THF, toluene, and dichloromethane. The reaction temperature is about -78 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5 -24 hours. In a preferred embodiment, compounds of formula (13) in THF at 0 °C were treated with lithium aluminum hydride, warmed to room temperature, and stirred for 3 hours to provide compounds of formula (14).

Compounds of formula (14) can be converted to compounds of formula (15) by the methods described in Scheme 1.

Scheme 3 (15) (14)

Compounds where Y is -NHC(O)- can be prepared as shown in Scheme 4. Conversion of compounds of formula (16) to compounds of formula (17) can be accomplished by treatment with a reducing agent. Representative reducing agents include Fe/HCl, Fe/NH₄C1, H/Raney Nickel, and H₂/Pd-C. Examples of solvents used in these reactions include ethanol, methanol, water, and isopropanol, or mixtures thereof. The reaction temperature is about 0 °C to 100 °C and depends on the method chosen. Reaction times are typically 0.5 to 24 hours. In a preferred embodiment, compounds of formula (16) in a mixture of ethanol and water are treated with Fe and NH₄C1, warmed to 70 °C, and stirred for 1 hour to provide compounds of formula (17).

Compounds of formula (17) can be converted to compounds of formula (18) by treatment with an appropriately substituted acyl chloride in the presence of base. Representative bases include pyridine, triethylamine, diisopropylamine, and imidazole. Examples of solvents used in these reactions include dichloromethane, carbon tetrachloride, chloroform, and 1 ,2-dichloroethane. The reaction temperature is about

-10 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (17) in dichloromethane at 0 °C are treated with a substituted acyl chloride and pyridine, stirred for 30 minutes, warmed to room temperature, and stirred for 1 hour to provide compounds of formula (18).

Conversion of compounds of formula (18) to compounds of formula (19) can be accomplished by treatment with an oxidizing agent. Representative oxidizing agents include hydrogen peroxide, m-CPBA, KMnO₄, and potassium peroxymonosulfate (OXONE^®). Examples of solvents used in these reactions include methanol, ethanol, water, dichloromethane, and chloroform, and mixtures thereof. The reaction temperature is about -10 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5 to 24 hours. In a preferred embodiment, compounds of formula (18) in a mixture of methanol and water at 0 °C are treated with potassium peroxymonosulfate (OXONE^®) and NaHCO₃, stirred for 1 hour, warmed to room temperature, and stirred for 18 hours to provide compounds of formula (19).

Conversion of compounds of formula (19) to compounds of formula (20) can be accomplished by treatment with hydroxylamine. Examples of solvents used in these reactions include THF, diethyl ether, MTBE, and dioxane. The reaction temperature is about 0 °C to 50 °C and depends on the method chosen. Reaction times are about 0.5 to 12 hours. In a preferred embodiment, compounds of formula (19) in THF at room temperature are treated with hydroxylamine and stirred for 3 hours to provide compounds of formula (20). Compounds of formula (20) can be converted to compounds of formula (21) by the methods described in Scheme 1.

Scheme 4

2 3

The preparation of compounds containing R and R substituents is shown in Scheme 5. Compounds of formula (20) can be converted to compounds of formula (21) by treatment with an acylating agent in the presence of base, followed by treatment with a hydroxyl protecting reagent. Representative acylating agents include methylsulfonyl chloride (L is -SO₂CH₃), p-toluenesulfonyl chloride (L is -SO₂-p-tolyl), benzenesulfonyl chloride (L is -SO₂Ph), and trifluroacetic anhydride (L is -C(O)OCF₃), while representative bases include pyridine, triethylamine, and diisopropylamine. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride. The reaction temperature is about 0 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5 to 24 hours. Representative hydroxyl protecting reagents are dihydropyran (P is tetrahydropyranyl), trimethylsilylchloride (P is trimethylsilyl), and chloromethyl methyl ether (P is methyl O-methoxy ether). Examples of solvents used in these reactions include dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. The reaction temperature is about 0 °C to 50 °C and depends on the method chosen. Reaction times are typically 0.5 to 12 hours. In a preferred embodiment, compounds of formula (20) in dichloromethane at room tempeature are treated with methanesulfonyl chloride (L is -SO₂CH₃) and pyridine, and stirred for 7 hours. The resulting product in dichloromethane was then treated with dihydropyran and p-toluenesulfonic acid and stirred for 1 hour to provide compounds of formula (21) (P is tetrahydropyran).

Conversion of compounds of formula (21) to compounds of formula (23) can be accomplished by treatment with appropriately substituted thiophenols of formula (22) in the presence of base. Representative bases include sodium hydride, lithium hexamethyldisilazide, and potassium tert-butoxide. Examples of solvents used in these reactions include DMSO, NMP, dioxane, and DMF. The reaction temperature is about 20 °C to 100 °C and depends on the method chosen. Reaction times are about 1 to 24 hours. In a preferred embodiment, compounds of formula (21) in DMSO are treated with sodium hydride and compounds of formula (22), and heated to 80 °C for 8 hours to provide compounds of formula (23).

Compounds of formula (23) can be converted to compounds of formula (24) by the methods described in Scheme 4. Compounds of formula (24) can then be converted to compounds of formula (25) following the procedures described in Scheme 1.

Scheme 5

(25) (24)

The instant invention will now be described in connection with certain preferred embodiments which are not intended to limit its scope. On the contrary, the instant invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the instant invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

Example 1 hydroxy(^,dRS^')-l-methyl-3-((4-phenoxyphenyl)sulfonyl propyl)formamide

Example 1A (^'2RSV4-(^'(4-phenoxyphenyl)sulfonyl^')-2-butanol A solution of l-(methylsulfonyl)-4-phenoxybenzene (1.0 g, 4.0 mmol) in THF (40 mL) at -78 °C was treated with n-butyllithium (2.5 M in hexanes, 1.6 mL), stirred for 15 minutes , treated with propylene oxide (257 μL), warmed to 23 °C over 16 hours, quenched with H₂O, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. Purification of the concentrate by flash column chromatography on silica gel with l:l/hexanes:ethyl acetate provided the desired product. MS (ESI) m/e 307 (M+H)⁺. Example IB tert-butyl tert-butoxycarbonyloxy(Y 1 RSV 1 -methyl-3-((4- phenoxyphenyDsulfonyDpropyDcarbamate A solution of Example 1 A (200 mg, 0.65 mmol) in THF (20 mL) at 0 °C was treated with tert-butyl N-(tert-butoxycarbonyloxy)carbamate (168 mg), triphenylphosphine (188 mg), and diethyldiazocarbodiimide (113 μL), warmed to room temperature, stirred for 2 hours, and concentrated. Purification of the concentrate by flash column chromatography on silica gel with 5:l/hexanes:ethyl acetate provided the desired product. MS (ESI) m/e 522 (M+H)⁺.

Example 1C l-f(Y3RSy3-fhydroxyamino^')butyl)sulfonylV4-phenoxybenzene A solution of Example IB (1.59 g, 3.05 mmol) in dichloromethane (20 mL) at 0 °C was treated with trifluoroacetic acid (5 mL), warmed to room temperature, stirred for 1 hour, concentrated, dissolved in ethyl acetate, washed with saturated NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated. Purification of the concentrate by flash column chromatography on silica gel with 95:5/dichloromethane:methanol provided the desired product. MS (ESI) m/e 322 (M+H)⁺.

Example ID hydroxyf(^'lRS l-methyl-3-(^ff4-phenoxyphenyl)sulfonyl^')propyl^')formamide A solution of Example 1C (820 mg, 2.55 mmol) in THF (50 mL) at 0 °C was treated with acetic formic anhydride (200 μL), stirred for 20 minutes, treated with saturated NaHCO₃, extracted with ethyl acetate, washed with brine, dried (Na₂SO₄), filtered, and concentrated. Purification of the concentrate by flash column chromatography on silica gel with 95 :5/dichlorome thane: methanol provided the desired product.

MS (ESI) m/e 350 (M+H)⁺; Η NMR (300 MHz, DMSO-d₆): δ 9.77 (bs, 0.5H), 9.37 (bs, 0.5H), 8.22 (s, 0.5H), 7.86 (d, 2.5H, J=8.1 Hz), 7.49 (t, 2H, J=8.1 Hz), 7.29 (t, 1H, J=7.8 Hz), 7.17 (dd, 4H, J=7.4, 1.1 Hz), 4.36-4.23 (m, 0.5H), 3.93-3.80 (m, 0.5H), 3.30-3.06 (m, 2H), 1.90-1.61 (m, 2H), 1.13 (d, 1.5H, J=6.6 Hz), 1.07 (d, 1.5H, J=6.6 Hz);

Anal. Calcd. for C_I7H₁₉NO₅S: C, 58.43; H, 5.48; N, 4.00. Found: C, 58.65; H, 5.73; N, 3.95.

Example 2 hvdroxyf f 1 RS 1 -methyl-3-f (4-f4- (trifluoromethoxylphenoxy^phenv sulfony propyDformamide The desired product was prepared by substituting methyl 4-(4- (trifluoromethoxy)phenoxy)phenyl sulfone for l-(methylsulfonyl)-4-phenoxybenzene in Example 1.

MS (ESI) m/e 432 (M-H)^";

Η NMR (300 MHz, DMSO-d₆): δ 9.76 (bs, 0.5H), 9.35 (bs, 0.5H), 8.22 (s, 0.5H), 7.89 (d, 2.5H, J=8.8 Hz), 7.48 (d, 2.5H, J=9.2 Hz), 7.29 (d, 2H, J=9.1 Hz), 7.22 (d, 2H, J=8.8 Hz), 4.36-4.24 (m, 0.5H), 3.94-3.80 (m, 0.5H), 3.30-3.07 (m, 2H), 1.90-1.63 (m, 2H), 1.13 (d, 1.5H, J=6.8 Hz), 1.07 (d, 1.5H, J=6.8 Hz);

Anal. Calcd. for C₁₈H₁₈F₃NO₆S: C, 49.88; H, 4.18; N, 3.23. Found: C, 49.99; H, 4.12; N, 3.19.

Example 3 dRS)-3-(f4-f4-fluorophenoxy)phenyl)sulfonyl)-l-methylpropyl(hydroxy)formamide

The desired product was prepared by substituting l-fluoro-4-(4- (methylsulfonyl)phenoxy)benzene for l-(methylsulfonyl)-4-phenoxybenzene in Example 1.

MS (ESI) m/e 368 (M+H)⁺; Η NMR (300 MHz, DMSO-d₆): δ 9.77 (bs, 0.5H), 9.37 (bs, 0.5H), 8.22 (s, 0.5H), 7.87- 7.84 (m, 2.5H), 7.36-7.22 (m, 4H), 7.15 (d, 2H), 4.31-4.26 (m, 0.5H), 3.88-3.83 (m, 0.5H), 3.31-3.07 (m, 2H), 1.88-1.65 (m, 2H), 1.13 (d, 1.5H), 1.07 (d, 1.5H); Anal. Calcd. for C₁₇H₁₈FNO₅S: C, 55.58; H, 4.94; N, 3.81. Found: C, 55.73; H, 5.14; N, 3.76.

Example 4 π R )- 1 -(Y4.4-dimethyl-2.5-dioxo- 1 -imidazolidinynmethyn-3-f f4- phenoxyphenvDsulfony propyhhydroxy^formamide

Example 4A tert-butyl ( 1 RVf f benzyloxy methylV3-(Y4-phenoxyphenyDsulfonyl)propyl( tert- butoxycarbonyloxy)carbamate The desired product was prepared by substituting benzyl (S)-(+)-glycidyl ether for propylene oxide in Examples 1A and IB.

Example 4B

phenoxyphenyPsulfonyDpropyDcarbamate A solution of Example 4 A (7.5 g) in methanol (75 mL) and acetic acid (7.5 mL) was hydrogenated at 60 psi in the presence of 10% Pd/carbon (0.75 g) for 4 hours. The reaction was filtered and concentrated to provide the desired product. MS (ESI) m/e 538 (M+H) ⁺.

Example 4C tert-butyl tert-butoxycarbonyloxy (( 1 R)- 1 -(C4.4-dimethyl-2.5-dioxo- 1 - imidazolidinyDmethyl>3-f( -phenoxyphenyl)sulfonyDpropyl)carbamate

A solution of Example 4B (1 g, 1.86 mmol) in THF (9 mL) at 0 °C was treated with 5,5-dimethylhydantoin (357 mg), triphenylphosphine (731 mg), and diethyldiazocarbodiimide (439 μL), warmed to room temperature, stirred for 5 hours, and concentrated. Purification of the concentrate by flash column chromatography on silica gel with 2: 1 /hexanes: ethyl acetate provided the desired product. MS (ESI) m/e 646 (M-H)^".

Example 4D riRVl-rf4.4-dimethyl-2.5-dioxo-l-imidazolidinyl^')methyD-3-f(^'4- phenoxyphenyl)sulfonyl)propyl(hvdroxy formamide

The desired product was prepared by substituting Example 4C for Example IB in Examples 1C and ID. MS (ESI) m/e 476 (M+H) ⁺;

Η NMR (300 MHz, DMSO-d₆): δ 9.72 (bs, 0.5H), 9.41 (bs, 0.5H), 8.36 (s, 0.5H), 8.31 (s, 0.5H), 8.23 (br, IH), 7.87-7.83 (m, 2H), 7.70 (br, 0.5H), 7.49 (t, 2H), 7.29 (t, IH), 7.19- 7.14 (m, 4H), 4.48-4.37 (m, 0.5H), 4.19-4.15 (m, 0.5H), 3.59-3.22 (m, 4H), 1.91-1.64 (m, 2H), 1.22 (s, 6H);

Anal. Calcd. for C₂₂H₂₅O₇N₃S: C, 55.57; H, 5.30; N, 8.84. Found: C, 55.52; H, 5.33; N, 8.75.

Example 5 hydroxyl^" riR)-3-((4-phenoxyphenyl1sulfonyl -f(3.4.4-trimethyl-2.5-dioxo-l- imidazolidinyDmethyDpropyDformarnide The desired product was prepared by substituting 1,5,5-trimefhylhydantoin for 5,5- dimethylhydantoin in Example 4. MS (ESI) m/e 490 (M+H) ⁺; 1H NMR (300 MHz, DMSO-d₆): δ 9.73 (bs, 0.5H), 9.41 (bs, 0.5H), 8.22 (s, 0.5H), 7.87-

7.83 (m, 2H), 7.69 (s, 0.5H), 7.49 (t, 2H, J=8.2 Hz), 7.28 (t, IH, J=7.4 Hz), 7.19-7.14 (m,

4H), 4.49-4.36 (m, 0.5H), 4.19-4.07 (m, 0.5H), 3.63-3.14 (m, 2H), 2.77 (s, 1.5H), 2.76 (s,

1.5H), 1.93-1.60 (m, 2H), 1.24-1.22 (m, 6H );

Anal. Calcd. for C₂₃H₂₇N₃O₇S: C, 56.43; H, 5.56; N, 8.58. Found: C, 56.52; H, 5.82; N,

8.42.

Example 6 N-C2-(formyl(^'hydroxy )amino)ethyl)-N-methyl-4-(^'4-pyridinyloxy)benzenesulfonamide

Example 6A ethyl (methyl((4-(4-pyridinyloxy phenyl)suIfonyDamino acetate A solution of sarcosine ethyl ester hydrochloride (3.1 g, 20 mmol) in dichloromethane (150 mL) was treated with triethylamine (6.13 mL, 44 mmol), cooled to 0 °C, then treated with 4-(4-pyridinyloxy)benzenesulfonyl chloride (6.74 g, 22 mmol) (WO 98/50348, p.30), stirred for 2.5 hours, and partitioned between water and dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried, filtered, and concentrated. The concentrate was suspended in dichloromethane, filtered, and the solid was washed with dichloromethane. The filtrate and washings were concentrated to provide the desired product. R_f 0.35 (95 : 5/dichloromethane : methanol) .

Example 6B N-f2-hydroxyethyl)-N-methyl-4-(^'4-pyridinyloxy^s)benzenesulfonamide A solution of Example 6A (2.39 g, 6.8 mmol) in THF (20 mL) was added dropwise over 15 minutes to a 0 °C solution of lithium aluminum hydride ( 0.39 g, 10.3 mmol) in THF ( 5 mL). The resulting suspension was stirred at 0 °C for 10 minutes, warmed to room temperature, and stirred for 3 hours. The reaction was cooled to 0 °C, treated sequentially with H₂O (500 μL), NaOH (1.5 mL), and H₂O (500 μL) , warmed to room temperature, stirred for 1 hour, poured into water, and extracted with ethyl acetate. The combined extracts were dried, filtered, and concentrated to provide the desired product.

Example 6C N-(^,2-fformyl(hydroxy)amino)ethyl)-N-methyl-4-(4-pyridinyloxy)benzenesulfonamide The desired product was prepared by substituting Example 6B for Example 1A in Examples IB- ID. mp: 113-115 °C; MS (ESI) 352 (M+H)⁺;

1H NMR (DMSO-d₆): δ 10.08 (bs, 1/2H), 9.70 (bs, 1/2H), 8.80-8.73 (m, 2H), 8.24 (s, 1/2H), 7.94-7.83 (m, 2.5H), 7.39 (s, IH), 7.36 (s, IH), 7.16-7.05 (m, 2H), 3.77-3.66 (m, 2H), 3.46-3.38 (m, 2H), 2.74 (s, 3H);

Anal. Calcd. for C_I5H₁₇N₃O₅SO.25 C₄H₈O₂-0.25 H₂O: C, 50.85; H, 5.20; N, 11.11; S, 8.48. Found: C,50.96; H, 5.10; N, 11.05; S, 8.68.

Example 7 N-r4-frr2RS )-2-(formylChydroxy^')amino^')-3-hydroxypropyl)sulfonyl phenyl)-4-

(trifluoromethoxy^'lbenzamide

Example 7A EZVS-^-nitrophenyDsulfanyD-Σ-propenyl tert-butyldimethylsilyl ether A solution of a 1.5: 1 mixture of (E) and (Z) 3-((4-nitrophenyl)sulfanyl)-2-propen- l-ol (3.53 g, 16.71 mmol) ( prepared according to the procedure described in JCS, Perkin Trans. I, 1974, 25) in dichloromethane (40 mL) at room temperature was treated with imidazole (2.28 g, 33.4 mmol) and tert-butyldimethylsilyl chloride ( 2.77 g, 18.4 mmol), stirred for 24 hours, and pardoned between dichloromethane and water. The organic phase was dried, concentrated, and purified by flash column chromatography on silica gel with 8: l/hexanes:ethyl acetate to provide the desired product. R_f: 0.8 (2: l/hexanes:ethyl acetate).

Example 7B 4-(YdEZy3-((tert-butyl(dimethyl)silyDoxyVl-propenyDsulfanyl)aniline A mixture of Example 7 A (1.0 g, 3.07 mmol) and NH₄C1 (0.16 g, 3.07 mmol) in 4: l/ethanol:water (15 mL) was heated to 60 °C then treated with Fe (1.37g, 24.5 mmol) in small portions. The suspension was warmed to 70 °C, stirred for 1 hour, then diluted with ethyl acetate and filtered through a pad of diatomaceous earth (Celite^®). The filtrate was washed with brine, dried, and concentrated to provide the desired product. R_f: 0.2 (4: 1 /hexanes: ethyl acetate).

Example 7C

N-f4-(rriEZV3-(^'rtert-butvhdimethvnsilvDoxyVl-propenvnsulfanvnphenyn-4-

(trifluoromethoxy)benzamide A solution of Example 7B (0.92 g, 3.0 mmol) in dichloromethane (10 mL) at 0°C was sequentially treated with pyridine (0.3 mL, 3.7 mmol) and 4-trifluoromethoxybenzoyl chloride (0.53 mL, 3.4 mmol), stirred for 30 minutes, warmed to room temperature, and stirred for 1 hour. The reaction was diluted with water and extracted with dichloromethane. The combined extracts were washed with saturated NaHCO₃, dried, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:l/hexanes:ethyl acetate to provide the desired product. MS (ESI) 501 (M+NH₄)⁺.

Example 7D

N-('4-(f(lEZ -3-hydroxy-l-propenyl)sulfonyl)phenyl)-4-(trifluoromethoxy)benzamide A suspension of Example 7C ( 1.34 g, 2.79 mmol) in 2: l/methanol:water (60 mL) at 0 °C was treated with potassium peroxymonosulfate (OXONE^®) (4.28 g, 6.97 mmol) and NaHCO₃ (0.58 g, 6.97 mmol), stirred for lhour, warmed to room temperature, and stirred for 18 hours. The suspension was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with l:2/hexanes:ethyl acetate to provide the desired product. MS (ESI) 402 (M+H)⁺.

Example 7E N-f4-fff2RSV3-hydroxy-2-(hydroxyamino)propyl1sulfonyDphenylV4- (trifluoromethoxylbenzamide A solution of Example 7D ( 0.4 g, 0.99 mmol) in THF (10 mL) at room temperature was treated with hydroxylamine (50% solution, 0.6 mL, 9.9 mmol), stirred for 3 hours, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried, filtered, and concentrated. The concentrate was recrystallized from ethyl acetate to provide the desired product. MS (ESI) 435 (M+H)⁺.

Example 7F N-^- rCΣRSVΣ- formyKhydroxylaminol-S-hydroxypropyπsulfonyDphenyl ^-

(trifluoromethoxy benzamide A solution of Example 7E (0.33 g, 0.77 mmol) in THF (15 mL) at -20 °C was treated with acetic formic anhydride ( 0.062 mL, 0.78 mmol) dropwise over 25 minutes. The reaction was warmed to 4 °C over 2 hours, diluted with water, and extracted with ethyl acetate. The combined extracts were washed sequentially with saturated NaHCO₃, water, and brine, dried, filtered, and concentrated to a volume of 5 mL. The mixture was treated with hexanes and the resulting precipitate was filtered to provide the desired product. mp: 196 °C (decomp.); MS (ESI) 463 (M+H) ⁺;

Η NMR (300MHz, DMSO-d₆): δ 10.77 (bs, IH), 9.81 (bs, 0.3H), 9.41 (bs, 0.7H), 8.15- 7.80 (m, 7H), 7.57 (d, J=9.0Hz, 2H), 4.98 (m, IH), 4.56 (m, 0.3H), 3.98 (m, 0.7H), 3.60- 3.30 (m, 4H); Anal. Calcd. for C₁₈H₁₇F₃N₂O₇S: C, 46.75; H, 3.70; N, 6.05. Found: C 46.46; H, 3.85; N, 5.96.

Example 8 N-f4-f (Y 1 RSi-2-f formylf hvdroxy minoV 1 - fhydroxymethyDethyl)sulfonyl)phenyl)benzamide

Example 8A N-f4-(Y 1 -f tert-butoxymethyDvinyPsulfanyDphenyPbenzamide The desired product was prepared by substituting 2-((4-nitrophenyl)sulfanyl)-2- propen-1-ol (JCS, Perkin Trans. I, 1974, 25) and benzoyl chloride for (2EZ)-3-((4- nitrophenyl)sulfanyl)-2-propen-l-ol and 4-trifluoromethoxybenzoyl chloride, respectively, in Examples 7A-C. MS (ESI) 400 (M+H) ⁺.

Example 8B

N-(4-((^'l- (^"Ctert-butylfdimethyl^')silyl^')oxy^')methyl)vinyl)sulfonyl)phenyl^')benzamide A solution of Example 8A (0.1 g, 0.25 mmol) in dichloromethane (3 mL) at 0 °C was treated with 70% m-CPBA (0.18g, 0.75 mmol), warmed to room temperature, stirred for 1 hour, diluted with dichloromethane, treated with 10% NaHSO₃ (10 mL), and extracted with dichloromethane. The combined extracts were washed with saturated NaHCO₃, dried, filtered, and concentrated to provide the desired product. MS (ESI ) 432 (M+H)⁺.

Example 8C N-(4-((( l RS ^^(Y-tert-butylfdimethvnsilvnoxyV 1 -

CfformyKhydroxylaminolmethyDethyDsulfonyπphenyDbenzamide The desired product was prepared by substituting Example 8B for Example 7D in Examples 7E and 7F. MS (ESI) 493 (M+H)⁺.

Example 8D

N-f4-ffαRSV2-fformylfhvdroxy minoVl- ⁽hydroxymethyDethyDsulfonyDphenyPbenzamide A solution of Example 8C (0.33 g, 0.6 mmol) in THF (12 mL) at room temperature was treated with acetic acid (0.037 mL) and tetrabutylammonium fluoride (1.0 M in THF, 0.97 mL, 0.97 mmol), stirred for 4 hours, and partitioned between water and ethyl acetate. The organic phase was washed with brine, dried, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 90: 10/dichlorome thane: methanol to 92: 8/dichloromethane: methanol to provide the desired product. MS (ESI) m/e 379 (M+H)⁺;

Η NMR (300MHz, DMSO-d₆): δ 10.70 (s, IH), 10.16 (bs, 0.4H), 9.70 (bs, 0.6H), 8.22 (bs, 0.4H), 8.06 (d, J=9Hz, 2H), 7.98 (d, J=7.5Hz, 2H), 7.88 (m, 2.6H), 7.68-7.52 (m, 3H), 5.08 (t, J= 4.5Hz, 0.6H), 4.95 (bs, 0.4H), 3.90-3.62 (m, 4H), 3.54 (m, IH).

Example 9

N-(4-(^'C(^'2RSV2-fformyl(^"hydroxy)aminoV3-hydroxypropyl^')sulfonyl^')phenyl)-4- pentylbenzamide The desired product was prepared by substituting 4-n-pentylbenzoyl chloride for 4-trifluoromethoxybenzoyl chloride in Example 7. MS (ESI) m/e 449 (M+H)⁺;

Η NMR (300MHz, DMSO-d₆): δ 10.67 (bs, IH), 9.91 (bs, 0.4H), 9.45 (bs, 0.6H), 8.15- 7.80 (m, 7H), 7.38 (d, J=8.1Hz, 2H), 5.1 (m, IH), 4.55 (m, 0.4H), 3.96 (m, 0.6H), 3.60- 3.30 (m, 4H), 2.66 (t, J=7.5Hz, 2H), 1.61 (m, 2H), 1.29 (m, 4H), 0.87 (t, J=6.6Hz, 3H).

Example 10

2.2-dimethyl-3-((4-phenoxyphenyDsulfonyDpropyl(hydroxy)formamide

Example 10A 2.2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate A solution of neopentyl glycol (5.0 g, 48 mmol), pyridine (5 mL) and methanesulfonyl chloride (4.3 mL) in dichloromethane (100 mL) at room temperature was stirred for 7 hours, then partitioned between brine and ethyl acetate. The organic phase was washed sequentially with saturated NaHCO₃, brine, dried (Na₂SO₄), filtered, and concentrated. The concentrate was dissolved in dichloromethane (100 mL), treated with dihydropyran (15.3 mL) and p-toluenesulfonic acid (457 mg),stirred for 1 hour, then treated with saturated NaHCO₃ and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO₄), filtered, concentrated and purified by flash column chromatography on silica gel with 2: 1 /hexanes: ethyl acetate to provide the desired product.

MS (ESI) 284 (M+NH₄)⁺.

Example lOB

2-f2.2-dimethyl-3-((^,4-phenoxyphenyl)sulfanyl)propoxy)tetrahydro-2H-pyran A solution of 4-phenoxybenzenethiol (4.0 g) in DMSO (30 mL) was treated with sodium hydride (60% oil dispersion, 790 mg) and a solution of Example 10A (4.39 g, 16.5 mmol) in DMSO (30 mL). The resulting mixture was heated to 80 °C, stirred for 8 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na₂SO₄), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 95:5/hexanes:ethyl acetate to provide the desired product. MS (ESI) 373 (M+H)⁺.

Example 10C 2.2-dimethyl-3-f f 4-phenoxyphenyl)sulfanylV 1 -propanol A solution of Example 10B (4.2 g, 11.27 mmol) in THF (10 mL) was treated with acetic acid (20 mL) and H₂O (5 mL), heated at 45 °C, stirred for 16 hours , cooled to 0 °C, treated with saturated NaHCO₃ and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5: l/hexanes:ethyl acetate to provide the desired product. MS (DCI) 289 (M+H)⁺.

Example 10D 2.2-dimethyl-3-f(4-phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide The desired product was prepared by substituting Example 10C for Example 7C in Example 7D, then substituting the resulting product for Example 1A in Examples IB-ID. MS (ESI) 364 (M+H)⁺; 'H NMR (DMSO-d₆): δ 10.10 (bs, 0.5H), 9.68 (bs, 0.5H), 8.30 (s, 0.5H), 7.90-7.86 (m, 2.5H), 7.51-7.45 (m, 2H), 7.30-7.25 (m, IH), 7.18-7.14 (m, 4H), 3.50 (s, IH), 3.47 (s, IH), 3.34 (s, IH), 3.34 (s, IH), 1.12 (s, 6H);

Anal. Calcd. for C_I8H₂₁NO₅S: C, 59.49; H, 5.82; N, 3.85. Found: C, 59.37; H, 5.79; N, 3.69.

Example 11 ( lR>3-((4-(4-chlorophenoxy phenyl sulfonyl 1 -(Y4.4-dimethyl-2.5-dioxo- 1 - imidazolidinyPmethyPpropylfhydroxylformamide The desired product was prepared by substituting 4-(4-chlorophenoxy)phenyl methyl sulfone for 4-phenoxyphenyl methyl sulfone in Example 4. mp: 162-163 °C; (α) ° -2° (c 0.2, CHC1₃); MS (ESI) 510 (M+H) ⁺;

Η NMR (DMSO-d₆): δ 9.68 (bs, 0.5H), 9.38 (bs, 0.5H), 8.33 (bs, 0.5H), 8.27 (bs, 0.5H), 8.23 (s, 0.5H), 7.88-7.86 (m, 2H), 7.71 (s, 0.5H), 7.54-7.52 (m, 2H), 7.22-7.18 (m, 4H), 4.46-4.39 (m, 0.5H), 4.17-4.1- (m, 0.5H), 3.59-3.51 (m, IH), 3.43-3.18 (m, 3H), 1.91- 1.82 (m, IH), 1.74-1.68 (m, IH), 1.23-1.22 (m, 6H);

Anal. Calcd. for C₂₂H₂₄ClN₃O₇S: C, 51.82; H, 4.74; N, 8.24. Found: C, 51.86; H, 4.74; N, 8.21.

Example 12 2.2-dimethyl-3-(Y4-f4- ftrifluoromethoxy)phenoxy^phenyDsulfonyDpropyl(hydroxy formamideThe desired product was prepared by substituting 4-(4-trifluoromethoxyphenoxy)benzenethiol for 4- phenoxybenzenethiol in Example 10. MS (ESI) 448 (M+H) ⁺;

Η NMR (DMSO-d₆): δ 9.75 (bs, 0.5H), 9.50 (bs, 0.5H), 8.31 (s, 0.5H), 7.93-7.88 (m, 2.5H), 7.50-7.47 (m, 2H), 7.32-7.21 (m, 4H), 3.50-3.47 (m, 2H), 3.34 (m, 2H), 1.12 (s, 6H).

Example 13 ( 1 RV3-(f 4-f4-fluorophenoxy)phenvnsulfonylV 1 -(Y3.4.4-trimethyl-2.5-dioxo- 1 - imidazolidinyl)methyl)propyl(hydroxy)formamideThe desired product was prepared by substituting 4-(4-fluorophenoxy)phenyl methyl sulfone for 4-phenoxyphenyl methyl sulfone and 1,5,5-trimethylhydantoin for 5,5-dimethylhydantoin in Example 4. mp: 105 °C. (CØ D +1.5(C 0.2, MeOH); MS (ESI) 508 (M+H) ⁺;

'H NMR (DMSO-d₆): δ 9.72 (s, 0.5H), 9.41 (s, 0.5H), 8.22 (s, 0.5H), 7.86-7.82 (m, 2H), 7.69 (s, 0.5H), 7.37-7.12 (m, 6H), 4.48-4.35 (m, 0.5H), 4.20-4.06 (m, 0.5H), 3.62-3.52 (m, IH), 3.44-3.14 (m, 3H), 2.77 (s, 1.5H), 2.76 (s, 1.5H), 1.96-1.66 (m, 2H), 1.24-1.22 (m, 6H);

Anal. Calcd for: C₂₃H₂₆N₃O₇SF 0.25 H₂O: C, 53.95; H, 5.21; N, 8.20. Found: C, 53.81; H, 5.42; N, 7.84.

Example 14 ( 1 R 1 -f f 4.4-dimethyl-2.5-dioxo- 1 -imidazolidinylimethyl V3-f f 4'-(^ytrifluoromethyl)f 1.1'- biphenyiy4-yl)sulfonyl)propylChydroxy)formamide The desired product was prepared by substituting 4'-fluoro(l,l'-biphenyl)-4-yl methyl sulfone for 4-phenoxyphenyl methyl sulfone in Example 4. mp: 125 °C; (OØ D +2.7 (c 0.6, MeOH); MS (ESI) 528 (M+H)⁺;

Η NMR (DMSO-d₆): δ 9.72 (s, 0.5H), 9.42 (s, 0.5H), 8.36 (s, 0.5H), 8.29 (s, 0.5H), 8.24 (s, 0.5H), 8.07-7.97 (m, 6H), 7.91-7.88 (m, 2H), 7.71 (s, 0.5H), 4.52-4.40 (m, 0.5H), 4.22-4.09 (m, 0.5H), 3.60-3.50 (m, 4H), 1.98-1.64 (m, 2H), 1.20 (s, 3H), 1.19 (s, 3H); Anal. Calcd for: C₂₃H₂₄N₃O₆SF₃-0.25 H₂O C, 51.92; H, 4.64; N, 7.89. Found: C, 51.58; H, 4.80; N, 7.76.

Example 15 (lRS)-2-(((4-C4-fluorophenoxy)phenyl)sulfonyl)methyl)cyclohexyl(hydroxy^')formamide

Example 15A

2-(f(^"4-fluorophenylisulfonyl methyl)cyclohexanol The desired product was prepared by substituting cyclohexene oxide and 4-fluorophenyl methyl sulfone for propylene oxide and l-(methylsulfonyl)-4-phenoxybenzene, respectively, in Example 1A.

Example 15B dRSV2-fff4-f4-fluorophenoxy phenyDsulfonyDmethyl)cyclohexanol A solution of Example 15A (2.08g, 7.6 mmol) in DMSO (25 mL) was added to a solution of 4-fluorophenol (1.29g, 11 mmol) and potassium tert-butoxide ( 1.37g, 12 mmol) in DMSO (25 mL). The mixture was heated to 120 °C, stirred for 6 hours, cooled to room temperature, and partitioned between water and ethyl acetate. The organic phase was dried (MgSO₄), concentrated, and purified by flash column chromatography on silica gel with 9: 1/ethyl acetate:dichloromethane to provide the desired product. MS (ESI) 365 (M+H)⁺.

Example 15C dRSV2-((^'(^'4-(^'4-fluorophenoxy^')phenyDsulfonyl')methyl)cyclohexyl(hydroxy)formamide The desired product was prepared by substituting Example 15B for Example 1A in Examples IB- ID. MS (ESI) 408 (M+H)⁺;

'H NMR (DMSO-d₆): δ 9.96 (bs, 0.5H), 9.51 (bs, 0.5H), 8.05 (bs, 0.5H), 7.94-7.80 (m, 2.5H), 7.36-7.11 (m, 6H), 4.72-4.66 (m, 0.5H), 3.86-3.74 (m, 0.5H), 3.54-3.30 (m, 2H), 2.41-2.25 (m, IH), 1.90-1.22 (m, 8H);

Anal. Calcd. for C₂₀H₂₂FNO₅S: C, 58.95; H, 5.44; N, 3.44. Found: C, 59.22; H, 5.77; N, 3.22.

Example 16 hydroxyrfS-Cr^-^-rtrifluoromethoxylphenoxylpheny sulfony methy -l.S-dioxan-S- vDmethyDformamide The desired product was prepared by substituting (5-(hydroxymethyl)-l,3-dioxan- 5-yl)methanol and 4-(4-trifluoromethoxyphenoxy)benzenethiol for neopentyl glycol and 4-phenoxybenzenethiol, respectively, in Example 10. MS (ESI) 492 (M+H)⁺;

Η NMR (DMSO-d₆): δ 9.90 (bs, IH), 8.31 (s, IH), 7.94-7.89 (m, 2H), 7.47 (d, 2H, J=9.3 Hz), 7.26 (dd, 4H, J=20.3, 8.9 Hz), 4.82-4.64 (m, 2H), 4.03-3.96 (m, 2H), 3.86 (s, 2H), 3.85-3.72 (m, 2H), 3.62-3.46 (m, 2H). Anal. Calcd. for C₂₀H₂₀F₃NO₈S: C, 48.88; H, 4.10; N, 2.85. Found: C, 48.83; H, 4.12; N, 2.86.

It will be evident to one skilled in the art that the instant invention is not limited to the forgoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims and therefore intended to be embraced therein. WHAT IS CLAIMED IS:

1. A compound of formula (I),

(I), or a pharmaceutically acceptable salt or prodrug thereof, wherein

R 1 and R 2 are independently selected from the group consisting of

(1) hydrogen,

(2) alkyl,

(3) alkenyl, (4) alkynyl,

(5) alkoxyalkyl,

(6) alkoxycarbonylalkyl,

(7) haloalkyl,

(8) hydroxyalkyl, (9) -(alkylene)-S(O)_p-alkyl, wherein p is zero to two,

(10) phenyl,

(11) phenylalkoxyalkyl,

(12) phenylalkyl,

(13) phenoxyalkyl, (14) -(alkylene)-N(R2o)SO2-phenyl, wherein R20 is hydrogen or alkyl,

(15) (heterocycle)oxyalkyl,

(16) -(alkylene)-S(O)_p-heterocycle,

(17) -(alkylene)-heterocycle,

(18) heterocycle, and

(19) -(alkylene)-NR⁶R , wherein for (15)-(18), the heterocycle is selected from the group consisting of

(a) pyridyl,

(b) pyrazinyl, (c) pyridazinyl,

(d) furyl,

(e) thienyl,

(f) isoxazolyl, (g) oxazolyl, (h) thiazolyl,

a covalent bond, -O-, alkylene of two to four carbon atoms, piperidineneyl, alkenylene of two carbon atoms, alkynylene of two carbon atoms, -S(O)_p-,and

-C(O)-, and

and wherein for (10)-(18), the phenyl and the phenyl part of the phenylalkoxyalkyl, the 0 phenylalkyl, -the (alkylene)-N(R )SO₂-phenyl, the phenoxyalkyl, and the -

(alkylene)-S(O)_p-phenyl, the heterocycle, and the heterocycle part of the (heterocycle)oxy alkyl, the -(alkylene)-heterocycle and the -(alkylene)-S(O)_p- heterocycle are optionally substituted with one, two, or three substituents independently selected from the group consisting of (a) alkyl,

(b) alkoxy,

(c) alkoxyalkyl,

(d) halo,

(e) haloalkyl, (f) hydroxy,

(g) hydroxyalkyl, (h) -(alkylene)-heterocycle, (i) -(alkylene)-phenyl, (j) -N(R²°)SO₂-alkyl, (k) phenyl, wherein the phenyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of

(i) cyano,

(ii) nitro, and (iii) halo,

(1) -C(O)OR²°, and

(m) -C(O)NR^xR^y, wherein R^* and R^y are independently selected from the group consisting of (i) alkyl,

(ii) phenyl, and

(iii) phenylalkyl, wherein for (ii) and (iii), the phenyl and the phenyl part of phenylalkyl are optionally substituted with substituents independently selected from the group consisting of

(a) halo, and

(b) alkoxy, and wherein for (19), R and R are independently selected from the group consisting of

(a) hydrogen,

(b) alkyl,

(c) cycloalkyl,

(d) cycloalkylalkyl, (e) alkanoyl,

(f) phenyl, and

(g) phenylalkyl, wherein for (f) and (g), the phenyl and the phenyl part of the phenylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of (i) alkyl, (ii) alkoxy, (iii) perfluoroalkyl, (iv) halo,

(v) haloalkyl, and

(vi) alkanoyl, or R and R , taken together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of

(a) morpholinyl,

(b) thiomorpholinyl, (c) thiomoφholinyl sulfone,

105 (d) pyrrolidinyl,

(e) piperazinyl,

(f) piperidinyl,

(g) succinimidyl,

(h) maleimidyl,

110 (i) glutarimidyl,

(j) phthalimidyl,

(k) naphthalimidyl,

and

wherein for (a)-(w), the groups defined by R and R , together with the nitrogen atom to which they are attached, are optionally substituted with one or two substituents independently selected from the group consisting of

(i) halo, 130 (ii) alkyl,

(iii) alkoxy,

(iv) phenoxy,

(v) phenylalkyl, and 135 (vi) benzyloxy;

R is selected from the group consisting of

(1) hydrogen,

(2) alkyl, 140 and

(3) hydroxyalkyl; or R 2 and R 3 , taken together with the carbon atom to which they are attached, form a dioxanyl ring; 145 or

R 1 and R 3 taken together with the carbon atoms to which they are attached form a 5, 6, or 7-membered saturated carbocyclic ring;

R and R are independently selected from the group consisting of 150 (1) hydrogen,

(2) alkyl,

(3) perfluoroalkyl,

(4) halo,

(5) haloalkyl, 155 (6) alkoxy,

(7) hydroxy,

(8) hydroxyalkyl,

(9) alkoxy alkyl, and

160 (10) nitro;

X is selected from the group consisting of (l) -CH₂SO₂-,

(2) -SO₂-, 165 and

(3) -NR 8 SO₂-, wherein R 8 is either hydrogen or alkyl; wherein each group is drawn with its left-hand end being the end which attaches to the

2 3 ccaarrbboonn ccoonnttaaiinning R and R , and its right-hand end being the end which attaches to the phenyl group; 170

Y is selected from the group consisting of

(1) a covalent bond,

(2) -O-,

(3) alkylene-of two to four carbon atoms, 175 (4) piperidineneyl,

(5) alkenylene of two carbon atoms,

(6) alkynylene of two carbon atoms,

(7) -SO₂-, (8) -NHC(O)-, 180 and

(9) -C(O)-;

Ar is selected from the group consisting of (1) phenyl, 185 (2) pyridyl,

(3) pyrazinyl,

(4) pyridazinyl,

(5) furyl,

(6) thienyl, 190 (7) isoxazolyl,

(8) oxazolyl,

(9) thiazolyl, and

(10) isothiazolyl,

195 wherein (1)-(10) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of

(a) alkyl,

(b) alkoxy, wherein the alkoxy can be optionally substituted with alkoxy,

(c) -(alkylene)-CO₂R⁸,

200 (d) -(alkylene)-NR R , wherein R and R are independently selected from the group consisting of

(i) alkyl,

(ii) phenyl, and 205 (iii) phenylalkyl, wherein for (ii) and (iii), the phenyl and the phenyl part of the phenylalkyl can be optionally substituted with one or two substituents independently selected from the group consisting of halo and alkoxy, (e) alkoxyalkyl, 210 (f) cyano,

(g) cyanoalkyl, (h) halo, (i) haloalkyl, (j) hydroxy, 215 (k) hydroxyalkyl, (1) thioalkoxy, (m) thioalkoxyalkyl, (n) phenylalkoxy, (o) phenoxy,

220 (p) phenoxyalkyl, (q) (heterocycle)oxy, (r) (heterocycle)oxyalkyl, (s) perfluoroalkyl, (t) perfluoroalkoxy,

225 (u) sulfinylalkyl, (v) sulfonylalkyl,

(w)

wherein A is selected from the group consisting of -CH₂-, -CH O- and

-O-, and B is selected from the group consisting of -C(O)- and -(C(R")₂)_V -, wherein

R" is either hydrogen or alkyl, and v is 1-3,

230 and

(x) -N(R )SO₂R , wherein R is selected from the group consisting of

(i) hydrogen,

(ϋ) alkyl, and

235 (iii) -N(R 8 )(R 12 ), wherein R 12 is hydrogen or alkyl, wherein for (q) and (r), the heterocycle part of (heterocycle)oxy, and (heterocycle)oxyalkyl are selected from the group consisting of (i) pyridyl, (ii) pyrazinyl,

240 (iii) pyridazinyl, (iv) furyl, (v) thienyl, (vi) isoxazolyl, (vii) oxazolyl,

245 (viii) thiazoloyl, and (ix) isothiazolyl, and wherein for (q) and (r), the heterocycle part of the (heterocycle)oxy and the

(heterocycle)oxyalkyl can be optionally substituted with one or two substituents 250 independently selected from the group consisting of

(i) alkyl,

(ii) alkoxy,

(iii) perfluoroalkyl,

(iv) halo, 255 (v) cyano,

(vi) cyanoalkyl,

(vii) haloalkyl, and

(viii) alkanoyl, 260 and wherein for (o) and (p), the phenyl part of the phenoxy and the phenoxy alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of

(i) alkyl, 265 (ii) alkoxy,

(iii) perfluoroalkyl,

(iv) halo,

(v) cyano,

(vi) cyanoalkyl, 270 (vii) haloalkyl, and

(viii) alkanoyl.

Claims

2. A compound according to Claim 1, wherein X is -CH₂SO₂-.

3. A compound according to Claim 2, wherein Y is a covalent bond.

4. A compound according to Claim 3 which is

( 1 R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4'-(trifluoromethyl)( 1,1'- biphenyl)-4-yl)sulfonyl)propyl(hydroxy)formamide.

5. A compound according to Claim 1, wherein X is -CH₂SO₂- and Y is -NHC(O)-.

6. A compound according to Claim 7 selected from the group consisting of N-(4-(((2RS)-2-(formyl(hydroxy)amino)-3-hydroxypropyl)sulfonyl)phenyl)-4- (trifluoromethoxy)benzamide, N-(4-(((lRS)-2-(formyl(hydroxy)amino)-l- (hydroxymethyl)ethyl)sulfonyl)phenyl)benzamide, and

N-(4-(((2RS)-2-(formyl(hydroxy)amino)-3-hydroxypropyl)sulfonyl)phenyl)-4- pentylbenzamide.

7. A compound according to Claim 2, wherein Y is -O-.

8. A compound according to Claim 7, wherein R is hydrogen.

9. A compound according to Claim 7, selected from the group consisting of N-(2-(formyl(hydroxy)amino)ethyl)-N-methyl-4-(4-pyridinyloxy)benzenesulfonamide, 2,2-dimethyl-3-((4-phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide, 2,2-dimethyl-3-((4-(4- (trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl(hydroxy)formamide, and hydroxy((5-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-l,3-dioxan-5- yl)methyl)formamide.

10. A compound according to Claim 7, wherein R is alkyl.

11. A compound according to Claim 10, selected from the group consisting of hydroxy((lRS)-l-methyl-3-((4-phenoxyphenyl)sulfonyl)propyl)formamide, hydroxy((lRS)-l-methyl-3-((4-(4-

(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl)formamide, and

( 1 RS)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)- 1 -methylpropyl(hydroxy)formamide.

12. A compound according to Claim 7, wherein R is -(alkylene)-NR R .

13. A compound according to Claim 12, selected from the group consisting of ( 1 R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4- phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide, hydroxy((lR)-3-((4-phenoxyphenyl)sulfonyl)-l-((3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl)formamide,

( lR)-3-((4-(4-chlorophenoxy)phenyl)sulfonyl)- l-((4,4-dimethyl-2,5-dioxo- 1- imidazolidinyl)methyl)propyl(hydroxy)formamide, and

(lR)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)-l-((3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl(hydroxy)formamide.

14. A compound according to Claim 7, wherein R and R , taken together with the carbon atoms to which they are attached, form a 5, 6, or 7-membered carbocyclic ring.

15. A compound according to Claim 14 which is (lRS)-2-(((4-(4-fluorophenoxy)phenyl)sulfonyl)methyl)-cyclohexyl(hydroxy)formamide.

16. A method of inhibiting matrix metalloproteinases in a mammal in recognized need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.

17. A compound selected from the group consisting of hydroxy(( 1 RS)- 1 -methyl-3-((4-phenoxyphenyl)sulfonyl)propyl)formamide, hydroxy((lRS)-l-methyl-3-((4-(4-

(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl)formamide, ( 1 RS)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)- 1 -methylpropyl(hydroxy)formamide, ( 1R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4- phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide, hydroxy(( lR)-3-((4-phenoxyphenyl)sulfonyl)- 1 -((3,4,4-trimethyl-2,5-dioxo- 1- imidazolidinyl)methyl)propyl)formamide, N-(2-(formyl(hydroxy)amino)ethyl)-N-methyl-4-(4-pyridinyloxy)benzenesulfonamide,

N-(4-(((2RS)-2-(formyl(hydroxy)amino)-3-hydroxypropyl)sulfonyl)phenyl)-4-

(trifluoromethoxy)benzamide,

N-(4-(((lRS)-2-(formyl(hydroxy)amino)-l-

(hydroxymethyl)ethyl)sulfonyl)phenyl)benzamide, N-(4-(((2RS)-2-(formyl(hydroxy)amino)-3-hydroxypropyl)sulfonyl)phenyl)-4- pentylbenzamide,

2,2-dimethyl-3-((4-phenoxyphenyl)sulfonyl)propyl(hydroxy)formamide,

(lR)-3-((4-(4-chlorophenoxy)phenyl)sulfonyl)-l-((4,4-dimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl(hydroxy)formamide, 2,2-dimethyl-3-((4-(4-

(trifluoromethoxy)phenoxy)phenyl)sulfonyl)propyl(hydroxy)formamide,

(lR)-3-((4-(4-fluorophenoxy)phenyl)sulfonyl)-l-((3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl)propyl(hydroxy)formamide,

( 1 R)- 1 -((4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl)-3-((4'-(trifluoromethyl)( 1,1'- biphenyl)-4-yl)sulfonyl)propyl(hydroxy)formamide,

(lRS)-2-(((4-(4-fluorophenoxy)phenyl)sulfonyl)methyl)cyclohexyl(hydroxy)formamide, and hydroxy((5-(((4-(4-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)methyl)-l,3-dioxan-5- yl)methyl)formamide.